Sarcoma family kinase activity is required for cortical spreading depression

Cephalalgia ◽  
2017 ◽  
Vol 38 (11) ◽  
pp. 1748-1758 ◽  
Author(s):  
Fan Bu ◽  
Yan Wang ◽  
Liwen Jiang ◽  
Dongqing Ma ◽  
John P Quinn ◽  
...  
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Kinase Activity ◽  
Brain Slices ◽  
Inhibitory Effect ◽  
Optical Signal ◽  
Migraine Aura ◽  
Aspartate Receptor ◽  
Kinase Phosphorylation ◽  
Pharmacological Manipulations

Objectives Sarcoma family kinase activity is associated with multiple diseases including ischemia and cancer; however, its role in the mechanism of migraine aura has been less well characterised. This study aims to investigate whether sarcoma family kinase is required for cortical spreading depression. Methods Cortical spreading depression was induced by topical application of K+ to the cerebral cortex and was monitored using electrophysiology in rats, and intrinsic optical signal in mouse brain slices. Drugs were perfused into the contralateral cerebral ventricle for pharmacological manipulations in rats. Western blot analysis was used for detecting the level of phosphorylated, and total, sarcoma family kinase in the ipsilateral cortex of rats. Key results The data demonstrate that a single cortical spreading depression in rats induced ipsilateral cortical sarcoma family kinase phosphorylation at the Y416 site. Deactivation of sarcoma family kinase by its inhibitor (3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1 H-pyrazolo[3,4- dpyrimidin-4-amine) suppressed the elevated enzyme activity and cortical susceptibility to cortical spreading depression. Interestingly, the inhibitory effect of the N-methyl-D-aspartate receptor antagonist NVP-AAM077 on cortical spreading depression was reversed by the sarcoma family kinase activator pYEEI (EPQY(PO3H2)EEEIPIYL), suggesting a link between this enzyme and N-methyl-D-aspartate receptors. Similarly, after deactivation of sarcoma family kinase, a reduction of sarcoma family kinase phosphorylation and cortical susceptibility to cortical spreading depression was observed with NVP-AAM077. Conclusions We conclude that activation of sarcoma family kinase is required for cortical spreading depression, and this process is regulated by recruiting N-methyl-D-aspartate receptors. This study provides novel insight for sarcoma family kinase function in the mechanism of migraine aura.

scholarly journals Sarcoma Family Kinase-Dependent Pannexin-1 Activation after Cortical Spreading Depression Is Mediated by NR2A-Containing Receptors

2020 ◽  
Vol 21 (4) ◽  
pp. 1269 ◽  
Author(s):  
Fan Bu ◽  
Lingdi Nie ◽  
John P Quinn ◽  
Minyan Wang
Keyword(s):  
Mouse Brain ◽  
Protein Interactions ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Regulatory Mechanism ◽  
Brain Slices ◽  
Pannexin 1 ◽  
Migraine Headaches ◽  
Aspartate Receptor ◽  
Channel Opening

Cortical spreading depression (CSD) is a propagating wave of depolarization followed by depression of cortical activity. CSD triggers neuroinflammation via the pannexin-1 (Panx1) channel opening, which may eventually cause migraine headaches. However, the regulatory mechanism of Panx1 is unknown. This study investigates whether sarcoma family kinases (SFK) are involved in transmitting CSD-induced Panx1 activation, which is mediated by the NR2A-containing N-methyl-D-aspartate receptor. CSD was induced by topical application of K+ to cerebral cortices of rats and mouse brain slices. SFK inhibitor, PP2, or NR2A–receptor antagonist, NVP–AAM077, was perfused into contralateral cerebral ventricles (i.c.v.) of rats prior to CSD induction. Co-immunoprecipitation and Western blot were used for detecting protein interactions, and histofluorescence for addressing Panx1 activation. The results demonstrated that PP2 attenuated CSD-induced Panx1 activation in rat ipsilateral cortices. Cortical susceptibility to CSD was reduced by PP2 in rats and by TAT-Panx308 that disrupts SFK–Panx1 interaction in mouse brain slices. Furthermore, CSD promoted activated SFK coupling with Panx1 in rat ipsilateral cortices. Moreover, inhibition of NR2A by NVP–AAM077 reduced elevation of ipsilateral SFK–Panx1 interaction, Panx1 activation induced by CSD and cortical susceptibility to CSD in rats. These data suggest NR2A-regulated, SFK-dependent Panx1 activity plays an important role in migraine aura pathogenesis.

scholarly journals Estrogen-dependent effects of 5-hydroxytryptophan on cortical spreading depression in rat: Modelling the serotonin-ovarian hormone interaction in migraine aura

Cephalalgia ◽  
2017 ◽  
Vol 38 (3) ◽  
pp. 427-436 ◽  
Author(s):  
Virginie Chauvel ◽  
Sylvie Multon ◽  
Jean Schoenen
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Cortical Excitability ◽  
Ovarian Hormones ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Cycle Phase ◽  
Migraine Aura ◽  
Potential Efficacy ◽  
Estrogen Withdrawal

Background Cortical spreading depression (CSD) is the likely culprit of the migraine aura. Migraine is sexually dimorphic and thought to be a “low 5-HT” condition. We sought to decipher the interrelation between serotonin, ovarian hormones and cortical excitability in a model of migraine aura. Methods Occipital KCl-induced CSDs were recorded for one hour at parieto-occipital and frontal levels in adult male (n = 16) and female rats (n = 64) one hour after intraperitoneal (i.p.) injection of 5-hydroxytryptophan (5-HTP) or NaCl. Sixty-five oophorectomized females were treated with estradiol- (E2) or cholesterol- (Chol) filled capsules. Two weeks later we recorded CSDs after 5-HTP/NaCl injections before or 20 hours after capsule removal. Results 5-HTP had no effect in males, but decreased CSD frequency in cycling females, significantly so during estrus, at parieto-occipital (−3.5CSD/h, p < 0.001) and frontal levels (−2.5CSD/h, p = 0.014). In oophorectomized rats, CSD susceptibility increased during E2 treatment at both recording sites (+5CSD/h, p = 0.001 and +3CSD/h, p < 0.01), but decreased promptly after E2 withdrawal (−4.7CSD/h, p < 0.001 and −1.7CSD/h, p = 0.094). The CSD inhibitory effect of 5-HTP was significant only in E2-treated rats (−3.4CSD/h, p = 0.006 and −1.8CSD/h, p = 0.029). Neither the estrous cycle phase, nor E2 or 5-HTP treatments significantly modified CSD propagation velocity. Conclusion 5-HTP decreases CSD occurrence in the presence of ovarian hormones, suggesting its potential efficacy in migraine with aura prophylaxis in females. Elevated E2 levels increase CSD susceptibility, while estrogen withdrawal decreases CSD. In a translational perspective, these findings may explain why migraine auras can appear during pregnancy and why menstrual-related migraine attacks are rarely associated with an aura.

scholarly journals Minimum conditions for the induction of cortical spreading depression in brain slices

2014 ◽  
Vol 112 (10) ◽  
pp. 2572-2579 ◽  
Author(s):  
Yujie T. Tang ◽  
Jorge M. Mendez ◽  
Jeremy J. Theriot ◽  
Punam M. Sawant ◽  
Héctor E. López-Valdés ◽  
...  
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Potassium Concentration ◽  
Brain Slices ◽  
Threshold Concentration ◽  
Brain Trauma ◽  
Extracellular Potassium ◽  
Migraine Aura ◽  
Extracellular Potassium Concentration ◽  
Intracellular Potassium Concentration

Cortical spreading depression (CSD) occurs during various forms of brain injury such as stroke, subarachnoid hemorrhage, and brain trauma, but it is also thought to be the mechanism of the migraine aura. It is therefore expected to occur over a range of conditions including the awake behaving state. Yet it is unclear how such a massive depolarization could occur under relatively benign conditions. Using a microfluidic device with focal stimulation capability in a mouse brain slice model, we varied extracellular potassium concentration as well as the area exposed to increased extracellular potassium to determine the minimum conditions necessary to elicit CSD. Importantly, we focused on potassium levels that are physiologically plausible (≤145 mM; the intracellular potassium concentration). We found a strong correlation between the threshold concentration and the slice area exposed to increased extracellular potassium: minimum area of exposure was needed with the highest potassium concentration, while larger areas were needed at lower concentrations. We also found that moderate elevations of extracellular potassium were able to elicit CSD in relatively small estimated tissue volumes that might be activated under noninjury conditions. Our results thus show that CSD may be inducible under the conditions that expected in migraine aura as well as those related to brain trauma.

Migraine

2020 ◽  
pp. 213-224
Author(s):  
Julio R Vieira ◽  
Richard B Lipton
Keyword(s):  
Chronic Migraine ◽  
Migraine With Aura ◽  
Cortical Spreading Depression ◽  
Migraine Without Aura ◽  
Spreading Depression ◽  
Headache Frequency ◽  
Motor Symptoms ◽  
Migraine Aura ◽  
Younger Age ◽  
Psychiatric Conditions

This chapter examines migraine. The incidence of migraine varies depending on multiple aspects, including age, sex, and the presence of aura. At an earlier age (younger than age ten), migraine initially affects more boys than girls, with migraine with aura (MA) occurring at a younger age than migraine without aura (MO). Later in life, when puberty starts, this relationship changes and it becomes more common in women than men. Migraine aura are focal neurological symptoms that typically occur prior to the onset of a headache due to a phenomenon called cortical spreading depression. The prevalence of migraine with aura vary between visual, sensory, or motor symptoms. It can also present as diplopia, slurred speech, aphasia, dizziness, vertigo, and hemiparesis. Moreover, the prevalence of migraine varies according to headache frequency. The chapter then looks at chronic migraine and menstrual migraine. It also explores several comorbidities associated with migraine, including many neurologic, medical, and psychiatric conditions.

scholarly journals High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression

2016 ◽  
Vol 37 (3) ◽  
pp. 890-901 ◽  
Author(s):  
Tsubasa Takizawa ◽  
Mamoru Shibata ◽  
Yohei Kayama ◽  
Toshihiko Shimizu ◽  
Haruki Toriumi ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Cortical Spreading Depression ◽  
Microglial Activation ◽  
Spreading Depression ◽  
High Mobility ◽  
High Mobility Group ◽  
Migraine Aura ◽  
Double Knockout ◽  
Activated Microglia ◽  
Important Mediator

Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1–TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.

Nitric oxide and prostaglandins interact to mediate arteriolar dilation during cortical spreading depression

1995 ◽  
Vol 269 (1) ◽  
pp. H176-H181 ◽  
Author(s):  
W. Meng ◽  
D. M. Colonna ◽  
J. R. Tobin ◽  
D. W. Busija
Keyword(s):  
Nitric Oxide ◽  
Cortical Spreading Depression ◽  
Brain Cortex ◽  
Spreading Depression ◽  
Inhibitory Effect ◽  
Onset Latency ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Oxide Synthase ◽  
Arteriolar Diameter

We examined whether blockade of prostaglandin synthesis by indomethacin could attenuate the effect of nitric oxide synthase (NOS) inhibition on cerebral arteriolar dilation during cortical spreading depression (CSD). CSD was induced by microinjection of 5% (670 mM) KCl onto the cerebral cortex of anesthetized adult rabbits. A closed cranial window and intravital microscopy were used to measure pial arteriolar diameter, and NOS activity was determined by the conversion assay of [14C]arginine to [14C]citrulline. CSD dilated pial arterioles by 47 +/- 3% (baseline = 80-88 microns) (n = 21, P < 0.05), and inhibition of NOS by NG-nitro-L-arginine (L-NNA) (15 mg/kg iv) reduced dilation during CSD by over one-half (n = 8, P < 0.05) without altering the onset latency to CSD. After indomethacin administration (15 mg/kg iv), CSD dilated arterioles from 73 +/- 2 to 152 +/- 6 microns (n = 4, P < 0.05). However, after administration of both indomethacin and L-NNA (n = 5), CSD-induced arteriolar dilation was not different from the situation where indomethacin alone was given. Thus indomethacin completely abolished the inhibitory effect of L-NNA on CSD-induced dilation. Administration of L-NNA inhibited NOS activity in brain cortex almost completely (n = 8, P < 0.05), whereas indomethacin itself had no effect (n = 8). In addition, L-NNA inhibited topical acetylcholine (10(-5) M)-induced arteriolar dilation (n = 3, P < 0.05), and this effect was not altered by indomethacin (n = 4). In summary, L-NNA reduced arteriolar dilation during CSD. However, after administration of indomethacin, L-NNA does not reduce CSD-induced arteriolar dilation.

Oxcarbazepine does not suppress cortical spreading depression

Cephalalgia ◽  
2010 ◽  
Vol 31 (5) ◽  
pp. 537-542 ◽  
Author(s):  
Ulrike Hoffmann ◽  
Ergin Dileköz ◽  
Chiho Kudo ◽  
Cenk Ayata
Keyword(s):  
Single Dose ◽  
Cortical Spreading Depression ◽  
Chronic Treatment ◽  
Spreading Depression ◽  
Screening Tool ◽  
Positive Control ◽  
Migraine Prophylaxis ◽  
Migraine Aura ◽  
Predictive Utility ◽  
Prophylactic Drugs

Background: Cortical spreading depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was shown to suppress cortical spreading depression, implicating spreading depression as a common therapeutic target in migraine prophylaxis. Materials and methods: In order to assess the negative predictive value of spreading depression susceptibility as a preclinical drug screening tool, we tested oxcarbazepine, an anti-epileptic ineffective in migraine prophylaxis. Valproate served as the positive control. Cortical spreading depression susceptibility was measured in rats using topical KCl or electrical stimulation. Results: Oxcarbazepine did not suppress spreading depression either after a single dose or after daily treatment for 5 weeks. As previously shown, valproate suppressed spreading depression susceptibility after chronic dosing, while a single dose was ineffective. Conclusions: These data provide further support for spreading depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed spreading depression models.

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